Cardiac Structural and Sarcomere Genes Associated With Cardiomyopathy Exhibit Marked Intolerance of Genetic Variation

Abstract

Background The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine due to uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss of function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation. Methods and Results We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5,000 individuals from the National Heart, Lung, and Blood Institute’s Exome Sequencing Project (ESP), as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to one individual. Cardiomyopathy associated genes exhibited a rate of nonsense variants 96.1% lower than other Mendelian disease genes. We tested the ability of in-silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the ESP data. Algorithms based on conservation at the nucleotide level (GERP, PhastCons) did not perform as well as amino acid level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the ESP data at prevalence higher than expected. Conclusions Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the ‘single gene’ causality model.

Genetics and Disease of Ventricular Muscle

“…With insights gained from sequence data in many thousands of individuals in the general population, it has now become apparent that, in fact, a substantial proportion of human coding sequence variants are rare. A good example of this was provided in the data reported by Pan et al (2012), who looked at SNPs in coding regions of 46 cardiomyopathy genes in more than 5000 individuals in the ESP database and found that 9103 (91%) of the 9974 total variants were rare (minor allele frequency ,1%) and that 5448 (60%) of these were novel and seen only in one individual. In traditional Sanger-sequencing studies of selected candidate genes, any single high-impact variants identified have been assumed to be pathogenic.…”

Assigning a Causal Role to Genetic Variants in Hypertrophic Cardiomyopathy

“…Even in a study as big as 5000 individuals, about half of the variants identified were unique to 1 individual. 2 In other words, a low allele frequency is a necessary, but in no way sufficient, criterion for a plausible disease-causing mutation in a dominant trait. Evolutionary conservation adds information, but it is a low bar because a high proportion of amino acid residues are conserved and because an impact of the mutation on the protein does not necessarily predict a causal role in a specific disease.…”

Recent Developments in the Genetics of Cardiomyopathies

“…It is therefore crucially important to determine the extent of natural genetic variation and to distinguish 'background noise', particularly on a population and ethnicity basis, to define how much is disease-associated and therefore disease-modifying and/or disease-causative. For example, a study of general population exome data from the National Heart, Lung, and Blood Institute's Exome Sequencing Project has demonstrated that previously disease-associated mutations in the HCM genes were present in a higher frequency than expected for a purely monogenic disease model [32].…”